Cinchonidine derivative

Scheme 6.112 Michael addition of thiophenol to an a,p-unsaturated imide catalyzed by cinchonidine-derived thiourea 116 and cinchonine-derived thiourea 117, the first representatives of this class of bifunctional hydrogen-bonding cinchona alkaloid-thioureas.

As (—)-cinchonidine-derived ammonium salts have been mainly used as chiral PTCs in monomeric cinchona-PTCs via the asymmetric alkylation of 1, and have generally shown better results than those of others [e.g., derived from (+)-cinchonine, (—(-quinine, and (+)-quinidine], the Park-Jew group primarily prepared (—) -cinchonidine derivatives to identify both the optimal linker and best relationship of attachment for the two cinchona units, and to compare catalytic efficiency with that of monomeric cinchona-PTCs. 

The effect of the nature of the cinchona alkaloid component was then investigated (Scheme 4.4). The cinchonine-derived PTC 9, which are in pseudoenantiomeric relationship to the cinchonidine-derived compound 7, produced the opposite... 

Recently, Corey and coworkers prepared the cinchonidine-derived bifluoride 20 from the corresponding bromide by passage of a methanolic solution through a column of Amberlyst A-26 OH- form, and subsequent neutralization with 2 equiv. of 1 N HF solution and evaporation (the modified method C in Scheme 9.5). The catalytic activity and chiral efficiency of 20 (dried over P205 under vacuum) have been demonstrated by the development of a Mukaiyama-type aldol reaction of ketene silyl acetal 21 with aldehydes under mild conditions, giving mostly syw-P-hydroxy-a-amino esters 22 as the major diastereomer with good to excellent enantiomeric excesses (Table 9.4) [23],... 

A characteristic feature of this solid-phase amino acid synthesis is the use of the phosphazene bases 53 and 54 for the PTC alkylation reaction [64, 65]. Because these compounds, which are soluble in organic media, do not react with alkyl halides, both alkyl halide and phosphazene bases can be added together at the start of the reaction, which is useful practically [65], Cinchonine and cinchonidine-derived salts, e.g. 25, were found to be very efficient catalysts. Under optimum conditions the alkylation proceeds with enantioselectivity in the range 51-99% ee, depending on the alkyl halide component [65], Seventeen different alkyl halides were tested. After subsequent hydrolysis with trifluoroacetic acid the corresponding free amino acids were obtained in high yield (often >90%). 

Use of the preformed Z-silyl enol ether 18 results in quite substantial anti/syn selectivity (19 20 up to 20 1), with enantiomeric purity of the anti adducts reaching 99%. The chiral PT-catalyst 12 (Schemes 4.6 and 4.7) proved just as efficient in the conjugate addition of the N-benzhydrylidene glycine tert-butyl ester (22, Scheme 4.8) to acrylonitrile, affording the Michael adduct 23 in 85% yield and 91% ee [10]. This primary product was converted in three steps to L-ornithine [10]. The O-allylated cinchonidine derivative 21 was used in the conjugate addition of 22 to methyl acrylate, ethyl vinyl ketone, and cydohexenone (Scheme 4.8) [12]. The Michael-adducts 24-26 were obtained with high enantiomeric excess and, for cydohexenone as acceptor, with a remarkable (25 1) ratio of diastereomers (26, Scheme 4.8). In the last examples solid (base)-liquid (reactants) phase-transfer was applied. 

Asymmetric nucleophilic addition to C=C double bonds (see also Chapter 4) can also proceed highly stereoselectively. Several examples of enantio- and diastereo-selective Michael additions with 99% ee for the resulting products have been described by the Corey group [19]. A cinchonidine-derived phase-transfer organo-catalyst (10 mol%) was used. 

Several types of modifiers have been shown to be successful. Common features are a basic nitrogen atom close to one or more stereogenic centers connected to an extended aromatic system. By far the best overall results are obtained with cinchonidine derivatives for an excess of the (R)- and with cinchonine derivatives for the (,S )-alcohols.7... 

Cinchonidine-derived quaternary ammonium phenoxides (e.g., 296) have been shown to catalyze vinylogous aldol-type reaction between benzaldehyde and 4-methyl-2-(trimethylsilyloxy)furan, leading to the formation of a 5-substituted butenolide in good yield and good ee% as can be seen in Equation (181) <2007CL8>. 

Dehmlow and coworkers screened several analogues of dnchona-based PTCs bearing an N-(9-anthracenylmethyl) group [17]. Especially, in the case of 2-isopropyl naphthoquinones, the nonnatural deazacinchonidine derivative catalyst 11 showed better results compared to those obtained with the natural cinchonidine-derived analogue 12, in terms of both the catalytic activity and the enantioselectivity (84% ee) in this reaction (Scheme 5.12). 

Recently, Chen and coworkers demonstrated that the cinchonine- or cinchonidine-derived thioureas, 63 and 66, respectively, were also able to catalyze the enantioselective... 

Asymmetric Michael additions can also be performed under phase-transfer conditions with an achiral base in the presence of a chiral quaternary ammonium salt as a phase-transfer agent. Conn and coworkers conducted the Michael addition of 2-propyl-l-indanone (13) to methyl vinyl ketone under biphasic conditions (aq 50% NaOH/toluene) using the cinchonine/cinchonidine-derived chiral phase-transfer catalysts (PTCs), 14a and 14b, as a catalyst (Scheme 9.5). However, only low to... 

Very recently, Lu and coworkers successfully applied aminocatalysis via the enamine intermediate to the Michael addition of cyclic ketones to vinyl sulfones 181 [56]. In the presence of the cinchonidine-derived primary amine salt 179, the Michael reactions between vinyl sulfones 181 and cyclic ketones 180 proceeded smoothly, affording the desired adduct 182 in very high yield and with excellent enantioselectivity (up to 97% ee) (Scheme 9.63). They also successfully applied this methodology to the synthesis of sodium cyclamate. However, this protocol gave poor yields and ee values for acyclic ketones. 

Using a polymer-supported cinchonidine derivative (105), Hodge and coworkers [58] evaluated the enantioselective Michael addition between methyl 1-oxoindan-2-carboxylate (106) and methyl vinyl ketone (107) to afford the S-enantiomer of the Michael adduct 108 (Scheme 6.28). Employing a glass tube reactor [1.4 cm i.d. x 36 cm (length)], sealed at one end, containing 15 g of PS-cinchonidine 105 (reactor volume = 28.9 ml), the authors introduced solutions of 106 (0.50 M) and 107 (0.53 M) in toluene from separate inlets at a total flow rate of 0.83 pi min ... 

Modifier The effect of the modifier structure is also quite similar to that found for a-ketoesters [7]. Cinchonidine derivatives and quinine lead to an excess of the (R)-hydroxy-acid while the pseudo-enantiomeric cinchona alkaloids (cinchonine and quinidine) give preferentially (S)-product but with much lower enantioselecdvity. Changing the substituent Y at C9 has only an effect on the degree of asymmetric induction but not its direction. OMe and OH are more effective than OAc or H. An interesting exception are the Nj alkylated Cd derivatives which are completely ineffective in the case of the ester. Here, N-methyl-Cd+Cr gives a small excess of the R-enantiomer while N-benzyl-Cd Cl leads an 33% excess of (S)-4-phenyl-2-hydroxybutyric acid ... 

Using molecular oxygen as the oxidizing agent, the Itoh group has achieved the enantioselective preparation of 3-allyl-3-hydroxyoxindole 90 (85% ee) under phase-transfer conditions with the cinchonidine derived catalyst 89 [54]. The oxindole 90 was further manipulated to a key intermediate that has been applied in a prior synthesis of the hexahydropyrroloindole CPC-1 [55] (Scheme 24). 

Another different approach for carrying out the enantioselective 1,3-DCR involves the addition of a chiral base in substoichiometric amoimt. Many cinchonine and cinchonidine derivatives as well as silver salts were essayed. The best conversions and more reproducible results were obtained when employing silver fluoride and the highest ee resulted in the reactions performed with chiral base 61 (Scheme 18) [57]. The reaction between N-all lidene glycine esters 3 and terf-butyl acrylate catalyzed by silver fluoride and the commercially available chiral base dihydrocinchonine 61 (Scheme 17) proceeded with high endo-diastereoselectivity and moderate enantioselectivity (up to... 

Finally, a primary amine directed enamine activation has been used for a highly enantioselective conjugate addition of cyclohexanones to l,l-bis(benzenesulfonyl) ethylene [144], The reaction, which is efficiently catalyzed by Cinchonidine-derived primary amine 100 (10-20 mol%) is carried out in CHCI3 at 0°C in the presence of benzoic acid as cocatalyst. As depicted in Scheme 2.46, an enantioselective synthesis of (5,5)-sodium cyclamate has been achieved following this methodology. 

Chiral y-amino acids and y-nitroesters have been prepared, under PTC conditions, from 4-nitro-5-styrylisoxazoles, derivatives efficiently used as cinnamate equivalents in the asymmetric Michael reaction with nitroalkanes[181]. The reaction is catalyzed by Cinchonidine-derived catalyst 122 (2-5 mol%) at low temperatures (-30 to 0°C) affording high selectivities not only with nitromethane but also with secondary and tertiary nitroalkanes as nucleophiles. As seen in Scheme 2.66, the... 

Cinchonidine-derived catalyst 173 (10 mol%) has been also employed in the asymmettic synthesis of 4-alkytiden glutamic acid derivatives through a tandem conjugate addition-eUminalion reaction between the Schiff base of glycine tm-butyl ester and activated aUytic acetates under PTC conditions using CsOHH O as base [276]. The reaction, which is performed at -78°C in allows the preparation... 

In 2009, Bernadi and Adamo designed 4-nitro-5-sttyrylisoxazole (66) as a novel Michael acceptor. The asymmetric conjugate addition of nitroalkanes to 66 in the presence of cinchonidine-derived PTC catalyst 8o afforded the addition adduct 67 with high enantioselectivity (97% enantiomeric excess). The 4-nitroisoxazole eore serves as an activator of the conjugated alkene and is readily derivatised to pharmaceutically valuable compounds, such as y-nitroesters and y-amino acids (Scheme 16.20). " ... 

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